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Targeting Evasion Factors: Discovery of novel antibodies for durable suppression of HSV reactivation

Award Number: R21AI195395
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/10/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Targeting Evasion Factors: Discovery of novel antibodies for durable suppression of HSV reactivation - ABSTRACT Chronically-reactivating HSV is an underserved disease. Beyond lesions suffered by affected individuals, reactivation results in risk of transmission to others, especially as subclinical reactivation occurs with high frequency. Further, the isolation of ACV resistant strains, the inability of long-term ACV treatment to fully control reactivation, and the emerging evidence for HSV infection as a risk factor for neurodegeneration provide strong rationale for development of novel therapies to reduce rates of reactivation. Promisingly, epidemiological and preclinical evidence supports the ability of antibodies to modify rates of reactivation. However, because reactivation takes place in individuals with endogenous antibodies, there is reason to believe that monoclonal antibodies (mAbs) with attributes distinct from those commonly induced by natural infection will be needed to provide optimal benefit in this challenging clinical setting. To this end, diverse viral glycoproteins function to evade host defenses, and targeting these activities could both interfere with viral pathogenesis and drive immune-mediated clearance. Glycoproteins E and I form a complex (gE/gI) thought to function by binding to the IgG Fc domain and sweeping virus-specific Ab off the surface of virions and infected cells for degradation. Glycoprotein C (gC) inhibits complement activation by binding C3b. Both glycoproteins facilitate cell-to-cell spread. Blocking these host evasion and viral spreading mechanisms through binding of mAb Fab domains at the same time as driving innate immune clearance mechanisms through the effector functions of the Fc domain has the potential to turn these evasion mechanisms from assets into vulnerabilities. We hypothesize that mAbs targeting viral evasion factors gE/gI and gC will exhibit both direct and indirect antiviral effects. They will inhibit the functions of these evasion factors and contribute to viral and infected cell clearance through Fc-domain dependent effector functions. These activities can be further enhanced by Fc engineering, synergistically increasing the contribution of multiple mechanisms of action to the antiviral effects of mAbs in vivo. Our objective is to initially isolate and then systematically optimize mAbs with antiviral activity in vivo in reducing reactivation in mouse and guinea pig models. The rationale for this project is supported by the clinically apparent need to improve Ab potency to achieve robust reduction of reactivation, and preliminary data that Fc engineering can substantially improve mAb antiviral activity in vivo.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $215,758 )
2026	2026	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	4/10/2026	NEW	$215,758
														Subtotal = $215,758

Grand Total All Awards = $215,758

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Targeting Evasion Factors: Discovery of novel antibodies for durable suppression of HSV reactivation

Award Number: R21AI195395

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/10/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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